Despite intensive research it remains unclear why some people are more attracted to alcohol and will drink more readily in response to stress. Current work on substance abuse has focused on why many individuals are more likely than others to seek and abuse various agents. This proposal is aimed at an understanding of brain mechanisms controlling behavioral traits that influence the degree to which individuals seek alcohol. The mechanisms will be studied by using an animal model. One important predictor of the propensity to abuse various substances is the physiological and behavioral response to stress. We have found that rats that differ in their response to stress also differ in the extent to which they will voluntarily ingest ethanol. Ethanol drinking appears to be mediated by asymmetric stress-responsive prefrontalcortex(PFC)dopamine pathways. Neuronal activity in these pathways is increased by exposure to stress. These pathways modulate brain regions that determine the rewarding effects of ethanol (the nucleus accumbens) as well as turning behavior (the striatum). The PFC is also an important regulator of the neuroendocrine response to stress. Turning behavior thus predicts the behavioral and neuroendocrine response to stress and the propensity to ingest ethanol. The fundamental hypothesis of this proposal is that individual variation in susceptibility to alcohol abuse is brought about through functional and biochemical differences in the PFC. Under Aim 1, studies will investigate how animals displaying differences in turning behavior and neuroendocrine responsiveness differ in spontaneous and stress- precipitated limited-access ethanol drinking. The studies in Aim 2 will use 6-hydroxy dopamine lesions to selectively damage dopamine neurons in the left or right side of the PFC. Lesioned animals will then be assessed for differences in spontaneous and stress-induced ethanol consumption. While stress has frequently been postulated to contribute to the etiology of alcohol abuse, its mechanisms are not well understood. The present proposal seeks to study brain mechanisms that determine variation in the stress response as important determinants of the response to ethanol.